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Two major molecular drivers\u2014somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants\u2014lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MSH3 (a key regulator of somatic expansion), HTT, or both. In Q111 HD mice (&gt;110 CAGs), which exhibit robust expansion, mHTT inclusions, and transcriptional dysregulation by 12 months, long-term MSH3 silencing blocked expansion, reduced inclusions, and reversed gene expression changes. HTT silencing alone had limited effect, but combined MSH3\/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based co-silencing of MSH3 and HTT as a disease-modifying strategy for HD.<\/jats:p>","DOI":"10.1101\/2025.06.24.661398","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T16:05:13Z","timestamp":1750867513000},"source":"Crossref","is-referenced-by-count":8,"title":["Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntington\u2019s disease pathogenesis in mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-2336","authenticated-orcid":false,"given":"Jillian","family":"Belgrad","sequence":"first","affiliation":[{"name":"UMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Summers","sequence":"additional","affiliation":[{"name":"UMass Chan Medical 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